On average, >90% of patients who suffer from a cardiac arrest die. Nearly all die unexpectedly from this leading cause of death, in part, because the essential components of standard CPR (S-CPR): manual chest compressions at a rate of 100/min, 1 to 1.5 inches in depth and positive pressure ventilations, are an inherently inefficient process, providing less than 25% of normal blood flow to the heart and brain. Despite intensive research, little or no improvement in outcomes has been observed for over half a century. This application builds upon our new understanding of ways to optimize blood flow to the heart and brain during CPR and promises to provide new hope for patients who suffer from sudden cardiac death. The proposed research is focused on using more recently developed intrathoracic pressure regulation (IPR) technology to test the hypothesis that by using a combination of sodium nitroprusside (SNP), a potent vasodilator, and mechanical, non-invasive CPR adjuncts like Active Compression Decompression (ACD) CPR and IPR (the combination of which we term e- CPR), we can significantly and further improve CPR-generated blood flow to the heart and brain when compared with currently available CPR techniques. ACD CPR utilizes a suction cup to actively lift the chest wall during the decompression phase to enhance the refilling of the heart in between compressions. IPR generates a continuous negative intrathoracic pressure between positive pressure ventilations which creates a vacuum within the thorax relative to the rest of the body that enhances venous blood return to the heart, increases cardiac output and systemic arterial blood pressure, lowers right atrial and pulmonary artery pressures, lowers intracranial pressure by immediate transference of the negative intrathoracic pressure to the brain, and increases cerebral perfusion pressure. A potent vasodilator like SNP can be used with ACD CPR and IPR devices in this setting only because of the marked increase in circulation and blood pressure afforded with the mechanical adjuncts. The specific aims of this research proposal are to: 1) further develop and refine the IPR device from a mechanical device requiring an external suction source, to a new device (eIPR) with an internal suction source that does not need to be removed post return of spontaneous circulation (ROSC) which enhances circulation post-ROSC by augmenting venous return, and 2) determine the effectiveness of eCPR using the novel eIPR device on hemodynamics and survival outcomes measures in an established animal model of a) ventricular fibrillation cardiac arrest and b) pulseless electrical activity (PEA). This unique combination of mechanical and pharmacological mechanisms has the potential to provide normal levels of circulation during cardiac arrest which can significantly improve long-term neurologically-intact survival rates. If successful, this theray will result in saving >10,000 more Americans each year from out of hospital cardiac arrest and a similar number of in- hospital survivors based upon the superior blood flow and the ability afforded by eCPR to perform prolonged CPR with normal physiology. PUBLIC HEALTH RELEVANCE: Based upon a combination of multiple newly discovered mechanisms to enhance circulation during CPR, the goal of this SBIR phase 1 application is to optimize an intrathoracic pressure regulation device for use with a novel pharmacological approach to improving brain and heart blood flow during cardiac arrest with the goal of improving neurologically intact survival. This technology is needed because high quality STD CPR provides less than 20% of normal blood flow to the heart and little more to the brain. Even in the most efficient emergency medical systems, less than 20% of all patients with an out-of-hospital cardiac arrest are discharged from the hospital with intact neurological function. Strikingly, the average national survival to hospital discharge after out-of-hospital cardiac arres has remained less than 5% for decades. This complex disease state remains the nation's #1 killer, claiming more than 1000 lives outside the hospital and 1000 lives inside the hospital each day in the United States alone. Improved circulation to the brain and other vital organs during CPR, especially when combined in an overall systems-based approach to pre and post-resuscitation care, has the potential to significantly reduce morbidity and mortality from cardiac arrest.